Epilepsy affects roughly 1% of the world'population. Among the drugs employed for control of epileptic seizures is valproic acid. Valproic acid (also referred to as VPA, valproate, or 2-propylpentanoic acid) is an effective anticonvulsant, but it has a short duration of action. More seriously, VPA suffers from serious side effects, among them sedation, potentially fatal hepatotoxicity, and teratogenicity. Hepatotoxicity is particularly a problem in young children, especially children on polytherapy. The VPA-induced hepatic fatality rate among the latter patient category is reported to be 1/500 (F. E. Dreifuiss et al., Neurology (1987), 37, 379-385). Valproic acid has been shown to induce neural tube defects in mice, and it is estimated that the risk of spina bifida among newborns of women taking VPA during pregnancy is 1-2% (Centers for Disease Control, Morbidity and Mortality Weekly Report (1983), 32(33), 438-439).
There has been a considerable effort to discover analogues of valproic acid that are equally effective, but that have a greater margin of safety. See, for example, H. Nau et al., PCT application WO 94/06743, wherein a variety of modifications to the alkyl chains of valproic acid are made, and the related U.S. Pat. No. 5,786,380, which is hereby incorporated in its entirety by reference.
With regard to teratogenicity, it has been reported that introduction of a triple bond into the 4-position of valproic acid greatly increases teratogenicity, but that this effect is largely confined to the S-(-) enantiomer. Addition of a methyl group to the end of the triple bond abolished teratogenicity, while maintaining anticonvulsant activity (H. Nau, R.-S. Hauck, K. Ehlers, Pharmacology & Toxicology (1991), 69, 310-321.) These results indicated that separation of teratogenicity and anticonvulsive activity was possible. Sedative side effects were also separated from anticonvulsant activity in some analogues (M. Elmazar, R.-S. Hauck, H. Nau, J. Pharm. Sci. (1993), 82, 1255-1288.)
Alpha-branched carboxylic acids with an alpha-fluorine are little known. P. Crowley et al., in European patent application EP 468681, refers to 2-ethyl-2-fluorobutanoic acid as a fungicide intermediate, and a method for its preparation. Takeuchi refers to several examples of this class of compound in a publication relating to methods of preparing tertiary alkyl fluorides (Y. Takeuchi et al., J. Org. Chem. (1993), 58(13), 3483-3485).
The valproic acid analogue 2-fluoro-2-propyl-4-pentenoic acid has also been reported. The compound was used as a probe for studies of valproic acid hepatotoxicity and metabolism. (W. Tang et al., Chem. Res. Toxicol. (1995), 8(5), 671-682; M. Jurima-Romet et al., Toxicology (1996), 112(1), 69-85; W. Tang and F. Abbott, Drug Metab. Dispos. (1997), 25(2), 219-227.) In the above references, the presence of the 2-fluoro substituent was reported to reduce hepatotoxicity relative to 2-propyl-4-pentenoic acid. Anticonvulsant, sedative or teratogenic properties of the fluorinated compound were not disclosed.
Alpha-fluorinated valproic acid, 2-fluoro-2-propylpentanoic acid, has also been reported (Ph.D. thesis of Wei Tang, University of British Columbia, 1996). The anticonvulsant activity and pharmacokinetics of this compound were studied, and its pharmaceutical potential was speculated upon (F. Abbott, W. Tang, J. Palaty, J. Pharmacol. Exp. Ther. (1997), 282, 1163-1172). The compound was reported to be less potent than VPA, and the hepatotoxic, sedative, or teratogenic properties were not disclosed.
Valproic acid analogues with terminal trifluoromethyl groups have been reported: 5,5,5-trifluoro-2-(3,3,3-trifluoropropyl) pentanoic acid (K. Yamaguchi and M. Taninaka, Japanese patent Application 4-21652 (1992), and 5,5,5-trifluoro-2-n-propyl pentanoic acid (Hiroshima et al., Japan. J. Psychopharmacol. (1992) 12, 427). These compounds, too, are less potent than VPA.